The waning promise of leptin in the obesity fight

Early signs that the hormone would lead to effective weight-loss drugs have been muddled. Some scientists remain hopeful, though.

When the so-called fat-controlling hormone leptin was first discovered, scientists predicted it would be the basis for a bonanza of new obesity-fighting drugs.

That was 15 years ago. Today, scientists are still trying to develop leptin-based weight-loss therapies, but progress has been slower than anticipated. That's because leptin appears to affect several biochemical pathways in the body, and scientists still can't agree on how, precisely, the hormone works.

Researchers do, however, know one thing about leptin: "It's way more complicated than we first thought," says Susan Fried, a professor of medicine at Boston University School of Medicine.

Leptin was discovered by happenstance in the mid-1990s, when researchers noted that mice with a mutation in the gene that carries instructions for making the hormone became rapidly obese. When given doses of the hormone, however, the mice quickly lost weight.

Back then, leptin's role seemed clear: When present, it told the mice to eat less. Thus, when it was absent, the mice ate with abandon, to the point of obesity.

Human studies at first appeared to confirm that simply giving people more leptin could lead to weight loss. In one study, published in the Journal of the American Medical Assn. in 1999, 73 obese adults given daily injections of 0.3 milligram of leptin for every kilogram of their body weight lost more than 15 pounds over 24 weeks. The study also suggested that the more leptin the better: Participants receiving just 0.1 milligram of leptin lost less than 2 pounds over the same period. The hormone thus appeared to promote weight loss but by no means to an earth-shattering extent.

Other study results complicated the picture. Scientists already knew from a 1996 report in the New England Journal of Medicine that obese people already had much higher levels of leptin than lean people.

To an extent, that made sense: Leptin is manufactured by fat cells, thus, the more fat cells a person has, the more leptin they produce. The Philadelphia researchers therefore concluded — and other studies have since confirmed — that in most cases of obesity, leptin genes are intact; the hormone has stopped doing its job. In other words, over time, obese people become resistant to leptin's appetite-curbing effects.

Changing leptin levels in the body may also complicate people's ability to lose weight, says obesity researcher Christos Mantzoros, a professor of medicine at Harvard Medical School. Many obese people who diet may lose weight initially and then struggle to keep the pounds off. Researchers suspect that this is because as fat disappears, leptin levels drop, signaling the brain that more food is needed. Trials are now investigating whether keeping leptin levels stable during weight loss, with pills or injections, would prevent dieters from rebounding to their initial weight.

Researchers also are continuing to investigate how leptin tells the brain what, when and how much to eat. Brain imaging studies show that leptin doesn't just contribute to a physical feeling of fullness in the gut; it also affects areas of the brain associated with feelings of reward.

And until recently, scientists believed that leptin acted solely on the hypothalamus, a region of the brain that regulates a number of bodily functions, including temperature, hunger, thirst and sleep. Then last year, researchers at Columbia University and Yale University reported that the hormone also affects the brain's serotonin system, a collection of neurons that govern mood.

The findings were further evidence that the emotional and physiological aspects of why we eat are tightly intertwined, says study author Tamas Horvath, a Yale professor of neurobiology and obstetrics and gynecology.

In mice, at least, leptin has other effects that may influence body weight. In a study published in the journal Cell Metabolism last year, researchers showed they could make certain brain cells more responsive to leptin — and this not only caused mice to eat less, it also prompted them to double their level of activity.

It's unclear what such findings will mean for people, but what is becoming increasingly clear is that leptin is not involved solely in food consumption and body weight. Preliminary studies have linked varying levels of the hormone to Alzheimer's disease, bone disease, diabetes, infertility and some forms of cancer.

The countless pathways and still-unclear mechanisms through which leptin works in the body have frustrated many researchers' hopes that the hormone would lead to an anti-obesity wonder drug. Though some, like Fried, continue to study the hormone in lab animals and humans in hopes that its effects on body weight will become better understood, "Most people," she says, "have given up on it."